Among the human alkaline phosphatases, tissue-nonspecific alkaline phosphatase (TNAP) is essential for bone matrix mineralization. The biological function of TNAP is to hydrolyze extracellular inorganic pyrophosphate (ePPi), which is an inhibitor of calcification. Low levels of ePPi have been associated with hyper-mineralization. There is a need for compounds that inhibit TNAP to prevent medical conditions associated with hyper-mineralization, for example, osteoarthritis, medial vascular calcification, and ankylosis.